An excellent review of some of the prior art methods for the treatment of cancer by the application of external electromagnetic energy, capable of generating heat in intracellular particles to induce selective thermal death of cancer cells, is provided for in U.S. Pat. No. 4,106,488 to Gordon. See also U.S. Pat. Nos. 4,590,922 and 4,690,130.
The Gordon patent reports that one common characteristic for all of the known techniques for treating cancer is that they are extracellular in scope, that is, the cancer cell is attacked and attempted to be killed through application of the killing force or medium outside of the cell.
Unfortunately, the extracellular approach has some longstanding and important limitations, not the least of which is the difficulty in penetrating the tough outer membrane of the cancer cell that is composed of two protein layers with a lipid layer in between. Of even greater significance is that to overcome the protection afforded the cell by the cell membrane in any extracellular technique, the attack on the cancer cells must be of such intensity that considerable damage is caused to the normal cells. This results in severe side effects upon the patient. These side effects have been found to limit considerably the effectiveness and usefulness of these treatments.
A safe and effective cancer treatment has been the goal of investigators for a substantial period of time. Such a technique, to be successful in the destruction of the cancer cells, must be selective in effect upon the cancer cells and produce no irreversible damage to the normal cells. In sum, cancer treatment must selectively differentiate cancer cells from normal cells and must selectively weaken or kill the cancer cells without affecting the normal cells.
It has been known that there are certain physical differences that exist between cancer cells and normal cells. One primary physical difference that exists is in the temperature differential characteristics between the cancer cells and the normal cells. Cancer cells, because of their higher rates of metabolism, have higher resting temperatures compared to normal cells. In the living cell, the normal temperature of the cancer cell is known to be 37.5.degree. Centigrade, while that of the normal cell is 37.degree. Centigrade. Another physical characteristic that differentiates the cancer cells from the normal cells is that cancer cells die at lower temperatures than do normal cells. The temperature at which a normal cell will be killed and become unable to perform normal cell functions is at a temperature of 46.5.degree. Centigrade, on the average. The cancer cell, by contrast, will be killed at the lower temperature of 45.5.degree. Centigrade. The temperature elevation increment necessary to cause death in the cancer cell is determined to be at least approximately 8.0.degree. Centigrade, while the normal cell can withstand a temperature increase of at least 9.8.degree. Centigrade.
It is known, therefore, that with a precisely controlled increment of heat, the cancer cells can be selectively destroyed before the death of the normal cells. On the basis of this known differential in temperature characteristics, a number of extracellular attempts have been made to treat cancer by heating the cancer cells in the body. This concept of treatment is referred to as hyperthermia. To achieve these higher temperatures in the cancer cells, researchers have attempted a number of methods including inducing high fevers, utilizing hot baths, diathermy, applying hot wax, and even the implantation of various heating devices in the area of the cancer.
At this time, none of the various approaches to treat cancer have been truly effective and all have the common characteristic of approaching the problem by treating the cancer cell extracellularly. The outer membrane of the cancer cell, being composed of lipids and proteins, is a poor thermal conductor, thus making it difficult for the application of heat by external means to penetrate into the interior of the cell where the intracellular temperature must be raised to effect the death of the cell. If, through the extracellular approaches of the prior hyperthermia techniques, the temperatures were raised so high as to effect an adequate intracellular temperature to kill the cancer cells, many of the normal cells adjacent the application of heat could very well be destroyed.
The Gordon patent, in an attempt to improve on the selectivity in killing cancer cells, disclosed a process wherein minute particles, capable of generation of heat upon application of electromagnetic energy, are injected intravenously, through the use of "suitable compatible liquid vehicles" which must sustain the particles in suspension for injection. Suitable vehicles are identified to include aqueous solutions of any body acceptable materials such as dextran, dextrose, saline or blood, as well as water alone. The minute particles suspended in the aqueous media are reported to be transported through the bloodstream and were found to be phagocytized by the cancerous cells to a far greater degree than, and in fact some cases to the possible exclusion of, their admittance into the normal cells.
With regards to improving on selectivity, liposomes and other lipid structures have been widely proposed for targeting of drugs to specific locations in the body. See, e.g. the discussion in parent and copending U.S. application Ser. No. 07/958,646, the teachings of which are incorporated by reference. There it is pointed out that liposomes are aqueous compartments enclosed by a lipid membrane bilayer. Such membrane structures allow liposomes to regulate the passage of an entrapped drug into the bloodstream, a feature that offers potential for improving drug effectiveness and reducing side effects associated with certain drugs. However, aqueous core liposomes have met with their own limited success owing, among other things, to the tendency of drug leakage from the liposomes prior to reaching the delivery site.
It was therefore recognized in U.S. application Ser. No. 07/958,646 that a need existed for a controlled size liposome therapeutic agent which was particulate in nature (i.e. a liposome with a uniform size inorganic particle core) which would improve on the problem of leakage from the liposome and offer additional advantages unique to a solid-core type construction. Accordingly, uniform size inorganic core liposomes were therein reported which demonstrated a much improved ability to specifically target and deliver drugs to tissue or organs over existing prior art methods. The liposomes of U.S. application No. 07/958,646 were also of unconventional design, comprising an inorganic core, an amphipathic organic compound, and an amphipathic vesicle forming lipid.
Accordingly, it is a general object of this invention to build upon the prior discovery reported in copending U.S. application Ser. No. 07/958,646 and develop a wave absorbing magnetic particle core liposome composition which substantially improves on selectivity and allows the particles to pass through specific physiological membranes, whereupon exposure to electromagnetic radiation, the selected cells or tissues are heated and destroyed.
A more specific object of this invention is to prepare uniform size wave absorbing magnetic particles that have a crystal structure that cause them to absorb electromagnetic wave energy and convert that energy to heat.
Still another objective of the invention is to provide a method of preparing a uniform size wave absorbing magnetic particle core liposome composition without requiring postliposome formation extrusion or other sizing procedures.
It is also an object of this invention to provide a wave absorbing magnetic particle core liposome coupled to novel phenyl lipids which additionally enhance the circulation time of the liposome in the bloodstream.